The incidence of HIV infection in the United States iincreasing fastest in women, particularly those of African American and Hispanic descent. Moreover, approximately 11% of AIDS cases reported to the CDC are women over the age of 50. The introduction of potent antiretroviral therapy (ART), particularly HIV protease inhibitors, has extended survival of HIV-infected patients. However, their use has been accompanied by the emergence of several metabolic complications, among them low bone mass. Although postmenopausal women are at high risk for bone loss and fractures, published studies of bone mass and mineral metabolism in HIV/AIDS patients have not included older women. We have observed that over 40% of minority postmenopausal HIV+ women have osteoporosis. It is therefore essential that future research specifically target this group. The pathogenesis of excess bone loss associated with HIV infection is complex. Low body weight, chronic illness, malnutrition, malabsorption, calcium and vitamin D deficiency, and especially in postmenopausal women, estrogen deficiency, may contribute. Bone loss may also result from pathophysiologic interactions between HIV infection and ART and osteoclasts, osteoblasts and other elements within the bone microenvironment. In this proposal, we will: 1. Establish the prevalence of osteoporosis and rates of bone loss; 2. Elucidate the pathogenesis of bone loss; and 3. Delineate the effects of ART on bone structure and turnover in HIV+ African American and Hispanic postmenopausal women. We will use standard and novel methods: dual energy X-ray absorptiometry, serum measurements of bone turnover markers and cytokines, in vitro assays of osteoclastogenesis utilizing peripheral blood mononuclear cells and marrow mononuclear cells, quantitative bone histomorphometry and micro-computed tomography of iliac crest bone biopsies obtained before and after initiation of ART. We will demonstrate that osteoporosis is more prevalent and rates of bone loss more rapid in HIV+ than normal postmenopausal women, that alterations in the RANK/RANKL/OPG osteoclast signaling system are central to the pathogenesis of the osteoporosis, and that ART, particularly regimens that include ritonavir, is important in causing the bone loss. The results of these studies will have important therapeutic implications for the management of the growing number of postmenopausal women with HIV/AIDS.